Epidemiological and laboratory data produced in previous phases of this research program have shown human gastric carcinogenesis to progress through a series of six stages in which morphological features and biochemical markers and biochemical markers of differentiation define the progression to malignancy. The progression from normal to neoplastic state takes place over a period of many years, under the combined influence of modulating forces including carcinogens, irritants, bacterial infection, protective agents, and genetic susceptibility. In the proposed studies, attempts will be made to identify critical genetic events in the development of gastric cancer, and to determine whether they are similar to those previously found in colorectal cancer as well as cancers of other tissues. The investigation will focus on specific markers of activation of selected proto-oncogenes and inactivation of suppressor gene putatively involved in the tumorigenesis process. Specific genetic endpoints to be studied are: the role of somatic mutations in ras genes during gastric carcinogenesis by elucidation of activating mutations in Ha-ras, Ki-ras and N-ras genes in DNA of gastric mucosa at each stage of development of gastric cancer; analysis of the p53 gene in DNA of gastric mucosa at various stages of tumorigenesis for allelic deletions or point mutations in highly conserved regions of the gene in order to determine whether inactivation of p53 gene function is involved in gastric carcinogenesis and the frequency of occurrence of the TPR-MET oncogene rearrangement and expression levels of c-MET in the various stages of gastric carcinogenesis.